The Poliovirus (PV) belongs to the enterovirus genus within the Picornaviridae family. These small RNA viruses have a single-stranded positive-sense RNA genome and are non-enveloped. They are subdivided into three serotypes: PV1, PV2 and PV3. Infection with PV is usually asymptomatic; however, 1-2% of the cases result in paralytic poliomyelitis where viral-induced destruction of motor neurons causes paralysis, generally in limbs, termed Acute Flaccid Paralysis (AFP). Of these AFP cases, 5-10% are lethal as the virus spreads to regions of the brainstem resulting in respiratory arrest and, ultimately, death. (For reviews of PV and pathogenesis, see, for example, Minor 1999; Racaniello 2006; Pfeiffer 2010.)
Today, poliomyelitis is on the verge of eradication with only 406 and 359 cases worldwide in 2013 and 2014, respectively. There are two vaccines available that have enabled this successful battle against PV: the Inactivated Poliovirus Vaccine (IPV) (Salk 1953) and the Oral Poliovirus Vaccine (OPV) (Sabin 1956). IPV consists of three formalin-inactivated (killed) wild-type (neurovirulent) PV strains from each serotype (typically Mahoney, MEF-1 and Saukett for PV1, PV2 and PV3, respectively). OPV is made up of three live attenuated strains called Sabin 1, Sabin 2 and Sabin 3. The Sabin strains are named after Albert Sabin, who generated the strains through serial passage of three parental wild-type viruses through cell culture and even whole organisms (Sabin 1973). Due to the ease of administration and low costs of OPV (John 2009), it was heralded by the World Health Organization (WHO) and Global Polio Eradication Initiative (GPEI) as the vaccine of choice for the eradication program in 1988 (WHO 1988). However, the use of OPV is at odds with eradication and the end game strategy because the OPV vaccine strains display reversion of the attenuated phenotype to neurovirulent and transmissible polioviruses (Henderson, Witte et al. 1964). These Vaccine-Associated Paralytic Poliomyelitis (VAPP) cases occur with a frequency of one case per 500,000 vaccines (John 2004). Furthermore, circulating Vaccine-Derived Polioviruses (cVDPVs) result when the reverted vaccine viruses become transmissible within a susceptible population. As OPV is now recognized as a potential source of poliomyelitis through the VAPP and cVDPV phenomena, there has been a call for the use of OPV to be eliminated if complete eradication of poliomyelitis is to be achieved. In fact, over the last decade, regulatory authorities have recognized that OPV use must be ceased for eradication of poliomyelitis (WHO 2005). With IPV, the vaccine immunogens are formalin-inactivated, and, therefore, VAPP and cVDPV are not observed with the use of this vaccine. However, the 20-fold higher cost of this vaccine renders it unfavorable for use in low- and middle-income countries (Heinsbroek and Ruitenberg 2010; Zehrung 2010). To that end, the WHO and its many collaborators have initiated multiple projects for the development of strategies to make IPV safer and more economical (Zehrung 2010; Hawken and Troy 2012; Resik, Tejeda et al. 2013).
IPV is indeed a safer alternative to OPV with respect to VAPP and cVDPV; however, the wild-type viruses that make up the vaccine could pose a threat to the global population during the post-eradication era in the event of accidental escape of these viruses from a manufacturing facility. Furthermore, upon eradication, wild-type polioviruses will be subject to stringent bio-containment regulations, which may further increase the costs of goods of this already expensive vaccine (WHO 2006; Verdijk, Rots et al. 2011). In fact, the WHO already stipulates the destruction of any wild-type PV strains from laboratories across the globe. These actions will presumably be enforced more vigorously as eradication draws nearer (WHO 2009). Development of IPV vaccines based on attenuated strains is a safer vaccine manufacturing procedure and mitigates risks of potential disease outbreaks in the case of industrial accidents. To that end, the production of an IPV based on attenuated strains has been proposed as a strategy for the safe and economical production of IPV for the post-eradication era. Multiple attenuated strains have been proposed as a basis for a novel IPV vaccine, of which most research has been invested in making an IPV from the Sabin strains (Verdijk, Rots et al. 2011). Sabin-based IPV has recently undergone a successful Phase II clinical trial as a stand-alone vaccine (Liao, Li et al. 2012) and a Phase II and III trial in combination with diphtheria, tetanus and acellular pertussis (DTaP) (Okada, Miyazaki et al. 2013). Moreover, in Japan, a Sabin-based IPV has recently been licensed in combination with DTaP (Mahmood, Pelkowski et al. 2013). However, the capsids of the Sabin viruses differ significantly from the conventional IPV wild-type viruses, and, upon formalin inactivation, Sabin viruses display different antigenic properties required to raise neutralizing antibodies (and, therefore, protection) against PV infection. Indeed, it has been observed that the immune response to Sabin IPV is altered as compared to the one raised against conventional IPV; therefore, different dosing of the vaccine is necessary (Westdijk, Brugmans et al. 2011).
Several rationally engineered attenuated PV strains exist; however, their potential as IPV vaccine strains has, as of yet, not been fully explored. One set of such candidate attenuated strains is based on genetically stabilized Sabin strains as superior live vaccine strains as compared to the Sabin strains for a novel OPV development, as well as use for a basis of a novel IPV (e.g., Macadam et al. 2006; WO 2008/017870; WO 2012/090000). These strains are capable of growth at physiological temperatures; however, they show significantly reduced infectivity at this temperature.
For the post-eradication era, there remains a need to develop an IPV based on safe, attenuated poliovirus strains, which do not revert to neurovirulent forms and which induce a similar immune response as conventional IPV based on wild-type strains.